AIDS, Acquired Immune Deficiency Syndrome, is such a Syndrome that humans are infected with human immunodeficiency virus, HIV, followed by immunodeficiency and a series of opportunistic infections and tumors are triggered, severe case of which can lead to death. According to the World Health Organization (WHO), there were 34 million HIV carriers and AIDS patients in the world in 2011, 2.7 million persons were newly infected and 1.8 million patients died. Chinese Center for Disease Control and Prevention estimated that there were 780000 HIV carriers and AIDS patients in China by the end of 2011, 48000 persons were newly infected and 28000 patients died. At present, China is facing high peak of AIDS morbidity and mortality.
At present, medicaments for treating AIDS in clinic are divided into following classes: reverse transcriptase inhibitors, including nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors; protease inhibitors; integrase inhibitors and entry inhibitors. Entry inhibitors can be divided into CCR5 antagonists, CXCR4 antagonists, adhesion inhibitors and fusion inhibitors according to different targets during the entry of HIV into host cells. So far the main therapy for the treatment of AIDS is highly active antiretroviral therapy (HAART) which advocates combination of several drugs acting on different stages of HIV replication to achieve effective anti-HIV effect. In the past decade, highly active antiretroviral therapy has largely reduced the mortality rate of HIV-infected patients. However, the dosage regimen of HAART is complex and drugs combination can cause long-term severe side effects. Therefore, the development of anti-HIV drugs having new action mechanisms has very important significance.
Chemokines are a class of cytokines guiding directed migration of lymphocytes and have an important role in inflammation, tissue repair, immune surveillance, extravasation of white blood cells, tumorigenesis and embryonic development. Chemokines are proteins belonging to a small molecule cytokine family which currently have about 45 members. Their common features are that they have small molecular weight (about 8-10 kDa) and they contain four position-conserved cysteine (Cys) residues to ensure tertiary structure. According to whether other amino acid is contained between two Cys close to N-terminal, the family is divided into four categories: CC, CXC, CX3C and C chemokine. Wherein, CC chemokine and CXC chemokine are the most important two categories.
The functions of chemokine are mediated by chemokine receptor in vivo. Currently, chemokine receptor is named according to the characteristics of chemokine bound specifically (for example, if its ligand belonged to a CC chemokine subfamily, then it is named CCR). Chemokine receptors belong to the seven transmembrane G-protein coupled receptors (GPCR), are selectively expressed on the surface of target cells, wherein N-terminal thereof is outside the cell and C terminal is in the cell, and they contain seven very conservative transmembrane region consisting of α-helix. So far 19 chemokine receptors have been found. They are CCR1-11, CXCR1-6, XCR1, and CX3CR1. Modulators of chemokine receptor can be used in a variety of diseases, such as inflammatory or allergic diseases and the like.
Studies have shown that CD4 molecule on Th cell is essential for HIV invasion, but only CD4 is not enough to mediate fusion of HIV with cell. Further researches have found that chemokine receptors involve in the HIV invasion process and are known as HIV coreceptors. Coreceptors can be divided into two categories. One is coreceptor CCR5 distributed on the surface of macrophages and involved in entrance of macrophage tropism (M-tropism) HIV into host cells. The other is coreceptor CCR4 distributed on the surface of T cell and involved in entrance of T cell tropism (T-tropism) HIV into host cells. In the initial stages of infection, almost all HIV-1 subtypes use CCR5 as a coreceptor. Therefore, CCR5 plays a very important role in the HIV infection.
It has been found in experiments in vitro that chemokine RANTES, MIP-1α and MIP-1β that can bind to CCR5 can inhibit HIV infection by inhibiting the M-tropism HIV from entering into cells. In the experiment, benign results were obtained bu knockouting gene expressing CCR5 in mice. However, some studies indicate that the immune function of mouse can be changed in some models. In 1996, it was reported that there are natural CCR5 gene-deficient homozygous individuals and such individuals can well protect themselves from HIV infection without any other health problems. Subsequently, it was found that compared with no CCR5 allele-deficient HIV-infected patients, heterozygous individuals with only one CCR5 allele can obviously delay the progression of AIDS. Therefore, CCR5 can be used as a good anti-HIV target.
Macromolecular CCR5 antagonist can bind specifically to the specific extracellular portion of CCR5 to produce inhibiting effects without major toxic effects, but it is unstable, easy to be digested and degraded, expensive, and can not be orally administrated nd even cause the body to produce antibody-induced immune response. Therefore, companies and research institutions have conducted a great deal of effective research on non-peptide small molecule CCR5 antagonist and developed a number of highly active small molecule CCR5 antagonists such as TAK-220, TBR652, Vicriviroc and Maraviroc (trade name Selzentry) approved for marketing by FDA in 2007.
In summary, there is an urgent need to develop compounds as CCR5 antagonist having potential drug use in the art.